The present invention relates to a method to prepare N-acyl derivatives of biphenyl alanine. N-acyl derivatives of biphenyl alanine are key intermediates in the synthesis of pharmaceutically active compounds, in particular neutral endopeptidase (NEP) inhibitors, such as those described in U.S. Pat. Nos. 4,722,810, 5,223,516, 4,610,816, 4,929,641, South African Patent Application 84/0670, UK 69578, U.S. Pat. No. 5,217,996, EP 00342850, GB 02218983, WO 92/14706, EP 0034391 1, JP 06234754, EP 00361365, WO 90/09374, JP 07157459, WO 94/15908, U.S. Pat. Nos. 5,273,990, 5,294,632, 5,250,522, EP 00636621, WO 93/09101, EP 00590442, WO 93/10773, WO2008/031567 and U.S. Pat. No. 5,217,996.
Typically, synthetic methods to prepare biphenyl alanine derivatives use expensive starting materials such as non-natural D-tyrosine. Moreover, said methods require the use of trifluoromethanesulfonic anhydride, which is also expensive, to activate the phenolic hydroxyl in order to carry out the aryl coupling reaction leading to the desired biphenyl structure. One example of such a synthetic approach is described in the Journal of Medicinal Chemistry 1995, Vol. 38 No. 10. 1689-1700. Scheme 1 illustrates one of these methods:

A method for preparing 2-acetylamino-3-biphenyl propanoic acid is reported in Chemical and Pharmaceutical Bulletin, 1976, 24 (12), 3149-57. Said method comprises the steps i) and ii) outlined below:
Step i)
Step ii)

A drawback of this process is that the acetyl group is removed under the reaction conditions of the first step and thus a further chemical step is necessary in order to reinstall it. Such an undesired acetyl removal makes thus the process unattractive both from the atom economic point of view and from the reagent cost perspective. Moreover, this process does not provide means to obtain enantiomerically pure 2-acylamino-3-biphenyl propanoic acid, in particular it does not allow for the preparation of (S)-2 acylamino-3-biphenyl acid, which is, as above mentioned, a key intermediate in the synthesis of pharmaceutically active compounds, in particular neutral endopeptidase (NEP) inhibitors.
Therefore, there is a strong need to develop inexpensive methods to prepare biphenyl alanine derivatives. It is found that the present invention meets this objective and thus provides a process that is industrially advantageous.